CDK Inhibitors And Their Use As Pharmaceuticals

A method of:

• inducing apoptosis in a cancer or tumor cell in a subject or a subject in need thereof, or inhibiting phosphorylation of Ser2RNAP2 in a cancer or tumor cell in a subject or a subject in need thereof;
• or
• reducing the level of induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) in a cancer or tumor cell in a subject or a subject in need thereof;
• or
• reducing the level of MYC protein in a cancer or tumor cell in a subject or a subject in need thereof;
• or
• inhibiting proliferation of a cancer or tumor cell in a subject or a subject in need thereof,
• the method comprising contacting the cancer or tumor cell with, or administering to the subject, an effective amount of a compound having Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
• wherein
• X1, X2, and X3 are each independently N or CR3;
• A1 is N or C—R4;
• B1 is C—R6R7, N—R5, O, or S;
• A2 is N—R8, S, or O;
• B2 is C—Rg or N;
• R1 is selected from C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-14 membered heteroaryl)-C1-4 alkyl, and (4-14 membered heterocycloalkyl)-C1-4 alkyl;
• wherein R1 is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected Rb substituents;
• R2, R3, R4, R5, R6, R7, R8 and R9 are each independently selected from H, D, halo, oxo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4alkyl, (5-14 membered heteroaryl)-C1-4 alkyl, (4-14 membered heterocycloalkyl)-C1-4 alkyl, CN, NO2, ORa1, SRa1, NHORa1, C(O)Ra1, C(O)NRa1Ra1, C(O)ORa1, OC(O)Ra1, OC(O)NRa1Ra1, NHRa1, NRa1Ra1, NRa1C(O)Ra1, NRa1C(O)ORa1, NRa1C(O)NRa1Ra1C(═NRa1)Ra1, C(═NRa1)NRa1Ra1, NRa1C(═NRa1)NRa1Ra1, NRa1C(═NOH)NRa1Ra1, NRa1C(═NCN)NRa1Ra1, NRa1S(O)Ra1, NRa1S(O)2Ra1, NRa1S(O)2NRa1Ra1, S(O)Ra1, S(O)NRa1Ra1S(O)2Ra1, SF5, P(O)Ra1Ra1, P(O)(ORa1)(ORa1), B(ORa1)2 and S(O)2NRa1Ra1;
• wherein when R2, R3, R4, R5, R6, R7, R8 or R9 is C1-6 alkyl, C1-6 alkoxy, C2-6alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4alkyl, (5-14 membered heteroaryl)-C1-4 alkyl, or (4-14 membered heterocycloalkyl)-C1-4 alkyl, then R2, R3, R4, R5, R6, R7, R8 or R9 is optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;
• or R4 and R5, together with the atoms to which they are attached, form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;
• or R6 and R7 together with the carbon atom to which they are both attached, form a C3-C7 spirocyclic ring;
• or R8 and R9, together with the atoms to which they are attached, form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;
• each Ra1 is independently selected from H, D, C1-6 alkyl, C1-4haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-14 membered heterocycloalkyl)-C1-4 alkyl;
• wherein when Ra1 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl- or (4-14 membered heterocycloalkyl)-C1-4 alkyl, then Ra1 is optionally substituted with 1, 2, 3, 4, or 5 independently selected Rd substituents;
• each Rb substituent is independently selected from D, halo, oxo, C1-4 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, (4-14 membered heterocycloalkyl)-C1-4 alkyl, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NRcC(═NOH)NRcRc, NRcC(═NCN)NRcRc, SF5, P(O)RcRC, P(O)(ORc)(ORc), NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)(═NRc)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc or S(O)2NRcRc;
• wherein when Rb is C1-4 alkyl, C1-6 alkoxy, C1-4haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl- or (4-14 membered heterocycloalkyl)-C1-4 alkyl, then Rb is optionally substituted with 1, 2, or 3 independently selected Rd substituents;
• each Rc is independently selected from H, D, —OH, C1-6 alkyl, C1-6 alkoxy, C1-4 haloalkyl, C2-6alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl;
• wherein when Rc is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl- or (4-10 membered heterocycloalkyl)-C1-4 alkyl, then Rc is optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents;
• each Rf is independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NR C(═NR)NRgRg, NRg C(═NOH)NRgRg, NRgC(═NCN)NRgRg, SF5, P(O)RgRg, P(O)(ORg)(ORg), S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRg S(O)2NRgRg, and S(O)2NRgRg;
• wherein when Rf is C1-4alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl, then Rf is optionally substituted with 1, 2, 3, 4, or 5 independently selected Rn substituents;
• each Rn is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NRo)NRoRo, NRoC(═NRo)NRoRo, NRoC(═NOH)NRoRo, NRoC(═NCN)NRoRo, SF5, P(O)RoRo, P(O)(ORo)(ORo), S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo;
• each Rd is independently selected from D, oxo, C1-6 alkyl, C1-6 haloalkyl, halo, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NR)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, SF5, P(O)ReRe, P(O)(ORe)(ORe), S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe,
• wherein when Rd is C1-6alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, or (4-10 membered heterocycloalkyl)-C1-4 alkyl, then Rd is optionally substituted with 1, 2, or 3 independently selected R substituents;
• each Re is independently selected from H, D, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl,
• wherein when Re is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl- or (4-10 membered heterocycloalkyl)-C1-4 alkyl, then Re is optionally substituted with 1, 2 or 3 independently selected Rg substituents;
• each Rg is independently selected from H, D, C1-6 alkyl, C1-4 haloalkyl, C2-6alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl,
• wherein when Rg is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl- or (4-10 membered heterocycloalkyl)-C1-4 alkyl, then Rg is optionally substituted with 1, 2 or 3 independently selected Rp substituents;
• each Rp is independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, and (4-10 membered heterocycloalkyl)-C1-4 alkyl, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, SF5, P(O)RrRr, P(O)(ORr)(ORr), S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr, and S(O)2NRrRr;
• each Ro or Rr is independently selected from H, D, C1-4 alkyl, C3-6cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C1-4 haloalkyl, C2-4alkenyl, and C2-4 alkynyl,
• wherein when Ro or Rr is C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, and C2-4 alkynyl, then Ro or Rr is optionally substituted with 1, 2 or 3 independently selected Rq substituents;
• each Rq is independently selected from D, OH, CN, —COOH, NH2, halo, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, —CONHR12, —NHC(O)R12, —OC(O)R12, —C(O)OR12, —C(O)R12, —SO2R12, —NHSO2R12, —SO2NHR12 and NR12R12,
• wherein when Rq is C1-6 alkyl, phenyl, 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, then Rq is optionally substituted with OH, CN, —COOH, NH2, C1-6 alkoxy, C3-6cycloalkyl or 4-6 membered heterocycloalkyl;
• and
• each R12 is independently C1-6 alkyl.